Syringomyelia, a cyst in the spinal cord, causes progressive paralysis in affected patients, including patients in childhood and early adulthood. Because the mechanism underlying the development and progression of syringomyelia has been unknown, there are a variety of current therapies, including surgery to open the spinal cord and the placement of drainage systems into the spinal cord. Understanding the mechanism causing syringomyelia may permit the identification of treatment that is more effective and less invasive. The purpose of this study is to establish the mechanism(s) of the progression of syringomyelia. A clinical study elucidating the basis of syringomyelia associated with the Chiari I malformation was recently completed in which the mechanism was shown, paradoxically, to be one that is outside the spinal cord by the following mechanism. The cerebellar tonsils and the brainstem act on a partially enclosed spinal subarachnoid space to generate cervical subarachnoid CSF pressure waves. These waves compress the spinal cord from without, not from within, as had previously been considered to occur, to propel the syrinx fluid downward with each heartbeat. Syrinx progression occurs as a consequence. Craniocervical decompression and duraplasty improved CSF flow at the foramen magnum in all patients. This, along with other observations made in the same study, indicated that successful treatment should not require entering the spinal cord al all. Successful surgery, by a procedure that does not invade the nervous system, eliminated the anatomic cause of the excess pressure waves and resulted in consistent resolution of syringomyelia. The demonstration of this mechanism should result in less invasive surgery and more effective treatment for this form of progressive paralysis. About 30% of patients with the Chiari I malformation have cough headache, a severe headache when they cough. Understanding the mechanism of cough headache may permit the identification of treatment that is more effective and less invasive. We recently completed a clinical study elucidating the basis of cough headache associated with the Chiari I malformation. The mechanism was shown to be that the Chiari I malformation obstructed the CSF pathways at the foramen magnum and reduced intraspinal compliance. Because of this, coughing produced abnormally high intrathecal pressure elevations in patients with cough headache and the Chiari I malformation. Successful surgery, by a procedure that does not invade the nervous system, relieved the obstruction of the CSF pathways at the foramen magnum, improved compliance, and relieved cough headache. The demonstration of this mechanism should result in less invasive surgery and more effective treatment for this form of debilitating headache. The process by which the Chiari I malformation develops is unknown. Ectopia of the cerebellar tonsils, which is the defining characteristic of the Chiari I malformation, may result because the posterior fossa does not develop to a normal size and is too small to accommodate a cerebellum of normal size. In a clinical study of families with multiple members affected by the Chiari I malformation, we are using MRI scans of the brain to evaluate for Chiari I malformation and to measure the size of the osseous structures and volume of the posterior fossa. After phenotyping family members as being affected or unaffected by these traits, we collect DNA specimens from them for genotyping. Finding a genetic locus for the Chiari I malformation would lead to a better understanding of the etiology of the Chiari I malformation, which may lead to ways to prevent it from occurring. Clinical and laboratory investigation of central nervous system vascular disorders: Delayed cerebral vasospasm is the most common cause of death or disability in patients with subarachnoid hemorrhage who survive to reach the hospital. We have investigated the mechanism of delayed vasospasm and examined new approaches for therapy of it. In a series of experiments, we have shown that two new approaches, a ferrous iron chelator and intracarotid infusion of a nitric oxide (NO) donor, reverse and prevent vasospasm after subarachnoid hemorrhage in primates. The intracarotid route of NO donor delivery was chosen after success with ICA delivery, but failure of intravenous infusion, of the NO donor to reverse or prevent vasospasm in primates. A pilot clinical study of intracarotid infusion of proliNO in humans has been approved by the IRB at the NIH and Fairfax Hospital Center for reversal of cerebral vasospasm after rupture of an aneurysm. We are waiting for the approval of this study from FDA after providing additional experimental toxicity data. Recently, we have demonstrated the presence of nitric oxide synthase-based dysfunction of the endothelium in a primate model of vasospasmTo further our understanding pathophysiology of vasospasm after SAH we study mechanism of endothelial dysfunction in vitro examining the influence of oxidized bilirubin products (BOXes) on production of ADMA and the effect of purported inhibitors of ADMA production. With the use of thrombolytic therapy for ischemic stroke, reperfusion injury has become an important issue, as it appears to underlie the risks associated with delayed treatment. We have shown that an intracarotid infusion of proliNO (a Nitric Oxide donor) a) quenches oxygen free radical production and b) reduces the volume of brain infarction in a rat model of global transient cerebral ischemia. Furthermore, in acute experiments with the rat model, we observed a significant decrease of stroke volume after intracarotid infusion of proliNO or an oxygen free radical scavenger Tempol. We continue to study influences of the NO donor in in vitro experiments to further our understanding of mechanism(s) of cellular protection against ischemia. Intracerebral Infusion in Patients with Medically Intractable Epilepsy: The hippocampus is the usual site of origin of medically intractable epilepsy. Relief of this type of epilepsy could occur if a method were developed to selectively suppress the epileptic focus within the hippocampus. After a successful experiment in a rodent model of epilepsy, and a non-human primate study, we are planning a clinical study of the infusion of muscimol into the hippocampus to temporarily inactivate the neurons of the epileptic focus. If this is successful, we will explore if agents can be used to permanently and selectively inactivate the epileptic focus. As a first step in the project, this year we finished a FDA-required study of the toxicity and distribution of the chronic infusion of muscimol into the hippocampus of 10 non-human primates. The infusions were tolerated without brain injury or permanent adverse effects. The clinical protocol will be initiated after the FDA reviews the data from the animal research study and removes the clinical hold status for the IND. Research Study of Specimens Obtained During Epilepsy. Temporal lobe tissue specimens that were removed to treat medically intractable epilepsy associated with mesial temporal sclerosis were subjected to extensive histological and virological evaluation. This evaluation demonstrated that medial temporal lobe tissue from some of these patients had elevated levels of human herpesvirus type 6 (HHV-6), suggesting a role for this virus in this chronic condition. A clinical study was completed that evaluated the functional activity and regional blood flow in cerebral cortex exposed during awake craniotomy to treat brain tumors and medically intractable epilepsy.